# In vivo role of the fibroblast in muscular dystrophy

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $349,800

## Abstract

Abstract
The muscular dystrophies are inherited disorders that largely affect striated muscle tissue resulting in
progressive muscle weakness, wasting, and in many instances, premature death. Many characterized
mutations in humans that cause muscular dystrophy (MD) result from alterations in structural attachment
proteins that affix the underlying contractile proteins to the basal lamina, providing rigidity to the skeletal
muscle cell membrane (sarcolemma). Loss of select attachment proteins in the dystrophin-glycoprotein
complex (DGC) permits contraction-induced membrane tears and influx of calcium that causes cellular
degeneration and necrosis of muscle fibers. During this necrotic process cytokines, chemokines and growth
factors are released as part of the inflammatory and repair process, although induction of fibrosis and scarring
are an unwanted side effect that worsens disease. One prominent cytokine is transforming growth factor-β
(TGFβ) that serves a master regulator of the fibrotic response and worsening of muscle pathology in MD.
While fibroblasts are directly regulated by TGFβ, no one has yet to examine the function of the fibroblast in
skeletal muscle directly in vivo, as a mediator or fibrosis and muscular dystrophy. Here we generated a unique
genetic model in the mouse that will selectively modulate the activity of the cardiac and skeletal muscle
fibroblast in vivo and in dystrophic mouse models of disease. Thus, here we will test the novel hypothesis
that myofibroblasts play a selective role in mediating fibrosis and tissue remodeling in heart and skeletal
muscle in response to cellular dropout from MD, while resident myofibers and cardiomyocytes in their
respective tissues underlie physiologic ECM / collagen production and basal lamina production during
development and as part of ongoing homeostasis. The application has 2 comprehensive specific aims: 1) To
genetically parse the role of myofibroblasts in skeletal muscle and heart during MD in the mouse, 2) To
examine how TGFβ, SMAD2/3 and p38α signaling mediate disease in MD through the myofibroblast in vivo.
The application will attempt to definitively address the function of the activated fibroblast (myofibroblast) in
muscle during MD disease onset and progression. It will also attempt to elucidate the importance of TGFβ
signaling in mediating myofibroblast formation and disease activity in vivo, as both canonical and non-
canonical pathways will be genetically dissected.

## Key facts

- **NIH application ID:** 9888312
- **Project number:** 5R01AR071301-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Jeffery D Molkentin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,800
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888312

## Citation

> US National Institutes of Health, RePORTER application 9888312, In vivo role of the fibroblast in muscular dystrophy (5R01AR071301-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9888312. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*